The primary aim of this project is to better understand the role of the HIV envelope protein to HIV pathogenesis. To that end, we have focused on the complex interplay between the viral envelope and several of the known cell surface receptors to which it binds. We are particularly interested in the role of envelope-mediated signal transduction in HIV pathogenesis. gp120 engages integrin &#945;4&#946;7, the gut-homing receptor, opens up many new and potentially important questions. Because &#945;4&#946;7 mediates leukocyte homing to gut associated lymphoid tissue, which is a principal site of HIV replication during the acute phase of infection we have set out to explore the role of &#945;4&#946;7 expressing CD4+ T cells in HIV transmission. We tested this hypothesis in a non-human primate model of HIV/SIV infection, and determined that an antibody specific for &#945;4&#946;7 prevented transmission in a rhesus macaque model of mucosal transmission. In addition, we have investigated the interaction between HIV and &#945;4&#946;7 on primary B cells. We have learned that some of the defects associated with HIV disease result from direct interactions between gp120 and receptors on B cells.